Project Summary: The long-term goal of my lab is to understand the signaling mechanisms by which chemoattractants regulate neutrophil functions and their roles in inflammation-related disease models. Chemoattractants stimulate production of reactive oxygen species (ROS) from neutrophils. ROS is chemically reactive and used by neutrophils to eliminate pathogens. It also exerts significant impact on the hosts. Most studies have shown that increases in ROS production are responsible for tissue damage that exacerbates disease conditions including many of the inflammation-related diseases. However, recent evidence, especially human genetic evidence, suggest that ROS's role may be much more complex than previously believed; it also plays a protective role. In the preliminary study of this application, we found that MAP3K2/3 can phosphorylate a key component of NADPH oxidase complex, which is a protein responsible for ROS generation in leukocytes. The elimination of MAP3K2/3 in leukocytes leads to increased generation of ROS and reduced lung damage in two mouse acute lung injury models, which is diminished by inhibiting ROS generation. We thus hypothesize that deactivation of MAP3K2/3 protects the lung against acute injury through a moderate increase in ROS release from leukocytes. In this study we will investigate the signaling mechanisms by which MAP3K2/3 inhibits ROS generation. We will also characterize how MAP3K2/3 inhibition reduces lung damage during acute lung injury and evaluate the therapeutic potential of a MAP3K2/3 inhibitor in mouse acute lung injury models. Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), in which leukocytes play an important role, are common syndromes with a high mortality rate with no effective pharmacological treatments. Thus, our study not only exerts strong impact in understanding of signaling mechanisms for ROS production regulation, but also may have an important clinical implication.